Darier disease: Golden era of discovery and global collaborations

Abstract

My mentee and I were pleased to read the comprehensive review by Ettinger et al.¹ on Darier disease (DD), a rare and complex genodermatosis. This article provides a valuable synthesis of current knowledge. Even after 15 years of studying and treating over 250 patients, some spanning four generations within the same family, I continue to encounter the profound clinical and therapeutic complexities of Darier disease.

We would like to highlight a few key topics discussed in the review.

DD has traditionally been viewed as a skin disease, but its systemic nature is now well recognized. Extracutaneous manifestations include neuropsychiatric disorders, learning disabilities, salivary gland obstructions and ocular abnormalities. The authors rightly emphasize the importance of early screening and multidisciplinary management to improve patient outcomes.

In 1999, Professor Alain Hovnanian's group identified ATP2A2 as the defective gene in DD.² This breakthrough revealed that mutations impair calcium homeostasis, disrupting keratinocyte adhesion and differentiation. This discovery has transformed diagnostic strategies and research directions. We wish to emphasize that genetic counselling, including ATP2A2 gene analysis and prenatal diagnostic options, should be offered to all patients.

The heterogeneity of DD lesions necessitates a standardized classification system. It is important to distinguish between classical and non-classical lesions. Classical DD lesions are common and disease-defining, including keratotic papules, pits, wart-like lesions and nail abnormalities. Non-classical DD lesions are rarer, affecting only a subset of patients, and include acral keratoderma, leucodermic macules, giant comedones, keloid-like vegetations and acral hemorrhagic blisters³ (Figure 1). This distinction may serve as the basis for a formal disease classification: classic DD (only classical lesions) and non-classical DD (at least one non-classical lesion). Distinguishing transient from persistent lesions is crucial for accurate treatment assessment. Recent findings link persistent lesions to second-hit somatic ATP2A2 mutations.⁴

DD is associated with a dysbiotic skin microbiome, with Staphylococcus species predominance.⁵ In my experience, bleach baths are highly effective in reducing bacterial colonization, preventing infections and minimizing odour. This simple, low-cost intervention should be more widely recommended.

The review highlights the inflammatory component of DD, particularly the IL-17A/IL-23A axis, shifting the focus beyond keratinocyte dysfunction. Monoclonal antibodies targeting IL-17A, IL-23A, IL-4 and IL-13 have shown promising results in case reports. However, as the authors rightfully stated, there is a lack of randomized placebo-controlled trials owing to the limited number of patients, and individual reports of successful treatments may not accurately reflect the overall picture.

Recognizing the urgent need for coordinated global research and collaboration, we established the International Task Force for Darier Disease (DD-ITF) in February 2025. This initiative brings together leading international experts on DD to develop consensuses on diagnosis, classification, assessments and to harmonize the management of patients worldwide.

We are honoured to have received the prestigious endorsement of the International League of Dermatological Societies (ILDS) and to collaborate with the European Reference Networks (ERNs). We warmly invite dermatologists with extensive clinical experience in managing DD to join our mission. Please contact us at [email protected].

DD research is entering an unprecedented golden era of discovery, driven by genomic advancements, emerging targeted therapies and international collaboration. By uniting the global dermatology community, we can transform DD patient care worldwide. Beyond dermatology, studying this rare disease may shed new light on the genetic foundations of neuropsychiatric disorders, opening the door to groundbreaking medical advancements.

Sofia Labbouz, MD. None. Roni P. Dodiuk-Gad: Consultant/investigator to the following companies: Sanofi, Regeneron Pharmaceuticals, AbbVie, Pfizer, Johnson & Johnson Innovative Medicine, Novartis, La Roche-Posay, Dexcel Pharma, Eli Lilly, Devintec Pharma, Mitsubishi Tanabe Pharma America, Sol–Gel Technologies Ltd.

The patients in this manuscript have given written informed consent to publication of their case details.